physicochemical factors affecting absorption

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FACILATED BY: Dr. PRAKASH RAO Pharma.technology (HOD) PRESENTED BY: YUGESH SHRESTHA Department of Pharma.technology SEMINAR ON PHYSICOCHEMICALFACTORS AFFECTING ABSORPTION

ABSORPTION:

ABSORPTION Drug absorption is defined as process of movement of unchanged drug from site of administration to systemic circulation. Hence the drug which is metabolized or chemically transformed at the site of application or transit by definition not absorbed. Generally bioavailability may be used to indicate the delivery of the active moiety from the site of administration to the target tissue or organ. Absorption often refers to the overall transport of drug into the body parts.

PHYSICOCHEMICAL FACTORS:

PHYSICOCHEMICAL FACTORS DRUG SOLUBILITY AND DISSOLUTION RATE SOLUBILITY Amount of a substance ( called the solute) that dissolves in a unit volume of a liquid substance (called the solvent ) to form a saturated solution under specified conditions of temperature and pressure . DISSOLUTION RATE Dissolution is pharmaceutically defined as the rate of mass transfer from a solid surface into the dissolution medium or solvent under standardized conditions of liquid/solid interface, temperature and solvent composition

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For instance ,a drug administered orally in tablet or capsule form it has to undergo disintegration and deaggregation rapidly. In order for a drug to be absorbed, it must get dissolved in the fluid at the absorption site. Thus the two critical slower rate determining process in the absorption of orally administered drugs are: - rate of dissolution. - rate of drug permeation through the bio membrane. NB: when dissolution is the controlling step in the overall process, absorption is said to be dissolution rate limited.

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Maximum absorbable dose (MAD) Maximum absorbable dose refers to the maximum amount of an orally administered drug that can be absorbed in the gastrointestinal tract. MAD is given by the following equation: MAD= K a S GI V GI t r where, K a = intrinsic absorption rate constanct S GI= the solubility of the drug in the GI fluid V GI = the volume of GI fluid present t r = residence of drug in GI

BIOPHARMACEUTICAL CLASSIFICATION SYSTEM: :

BIOPHARMACEUTICAL CLASSIFICATION SYSTEM : high SOLUBILTY low high PERMEABILITY 1 2 solubility permeability 3 4 low

Brief idea about BCS::

Brief idea about BCS: CLASS SOLUBILTY PERMEABILITY ABSORPTION Rate Limiting Step EXAMPLES ❶ HIGH HIGH WELL ABSORBED Gastric Emptying Acetaminophen,metoprolol,NsAIDS,verapamil,etc. ❷ LOW HIGH VARIABLE Dissolution Carbamazepine,digoxin, grieseofulvin,spironolactone,etc. ❸ HIGH LOW VARIABLE Permeability Bi sphosphonates,captopril , insulin,furosemide,etc . ❹ LOW LOW POORLY ABSORBED Case by case Neomycin, taxol,etc.

THEORIES OF DRUG DISSOLUTION:

THEORIES OF DRUG DISSOLUTION Dissolution is a process in which a solid substances solubilise in a given solvent. Several theories to explain drug dissolution are given below: - diffusion layer theory -danckwert’s model -double-barrier / interfacial barrier model Diffusion layer theory : This is the simplest and the most common theory for dissolution where drug moves from a higher concentration to lower concentration.

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the dissolution of a substance may be described by the NOYES-WHITNEY equation: Where: dW / dt is the rate of dissolution. A is the surface area of the solid. C is the concentration of the solid in the bulk dissolution medium. Cs is the concentration of the solid in the diffusion layer surrounding the solid. D is the diffusion coefficient . L is the diffusion layer thickness.

b. Particle size and effective surface area:

b. Particle size and effective surface area Particle size and surface area of a solid drug are inversely related to each other. Two types of surface area: Absolute surface area Effective surface area From the Noyes-Whitney equation, Larger the surface area , higher the dissolution rate. Since the surface area increases with decreasing particle size which can be accomplished by micronisation resulting higher dissolution. Eg : the griseofulvin dose was reduced to half and that of spironolactone was decreased by 20 times following micronisation .

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However micronisation actually decreases effective surface area of hydrophobic drugs like aspirin, phenacetin,phenobarbital etc. Reasons: - the hydrophobic surface of the drug adsorbs air onto their surface . - the particles reaggreagate to form large particles. - electrically induced agglomeration. REMEDY: Use of surfactant as wetting agent. Adding hydrophilic diluents such as PEG,PVP,dextrose etc.

c. POLYMORPHISM AND AMORPHISM:

c. POLYMORPHISM AND AMORPHISM INTERNAL STRUCTURE OF A COMPOUND crystalline noncrystalline Polymorphs molecular adducts nonstoichiometric stoichiometric enantiotropic monotropic complex complex organic solvates hydrates

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When a substance exists in more than one crystalline form, the different forms are designed as polymorphs and the phenomenon is called polymorphism. The existence of polymprphs can be determined by using techniques such as Optical crystallography X-ray diffraction Differntial scanning calorimetry . The polymorphs differ from each other with respect to their physical properties such as: Solubility Density Melting point Compression characters

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Stable state one of the several forms of polymorphs which is physically more stable than the others representing - the lowest energy - highest melting point and -least aqueous solubility. The remaining polymorphs are called as metastable form which represent -the higher energy state -lower melting point and -higher aqueous solublities. Since the metastable form shows greater aqueous solubilty,they show better bioavailabity and preferred in formulations. Amorphous form: the drug which is not having internal structure possessing highest form of energy and can be considered as super cooled liquids. They have greater aqueous solubility than the crystalline form. E.g. amorphous form of novobiocin is 10 times more soluble than the crystalline form Thus the order of dissolution of different solid forms of drug is, amorphous › metastable › stable

@:

@ Plot of Cp Vs Time for three formulations of Chloramphenicol palmitate Chloramphenicol palmitate is one example which exists in at least two polymorphs. The B form is apparently more bioavailable. The recommendation might be that manufacturers should use polymorph B for maximum solubility and absorption.  

d.Hydrates and solvates:

d.Hydrates and solvates The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates and the trapped solvent is called solvent of crystallization. The solvates can exist in different crystalline form called as pseudo polymorphs, the phenomenon is called as pseudo polymorphism . When the solvate in association with the drug is water, the solvate is known as hydrates which is common form of solvate form. Generally, the anhydrous form of a drug has greater aqueous solubility than hydrates.

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e.g. the anhydrous form of theophylline and ampicillin have higher aqueous solubility , dissolve at a faster rate and show better bioavailability in comparison to their monohydrate and trihydrate forms respectively . Similarly the organic solvates have greater aqueous solubility than the non solvates e.g. chloroform solvate of griseofulvin are more water soluble than their non – solvated forms.

e.Salt form :

e.Salt form Most drugs are weak acids or weak bases.one of the easiest approaches to enhance the solubility and dissolution rate of such drugs is to convert them into their salt forms. One more important thing to be note is that the dissolution rate of a particular salt is usually different from that of parent compound. Sodium or potassium salts of weak acids dissolves more rapidly then the free acids , regardless of the ph of dissolution medium.

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At given pH, the solubility of drug, whether acidic/basic or its salt form, is a constant. While considering the salt form of drug, pH of the diffusion layer is important not the pH of the bulk of the solution. Example of salt of weak acid. - It increases the pH of the diffusion layer, which promotes the solubility and dissolution of a weak acid and absorption is bound to be rapid. Dissolution and absorption of an acidic drug administered in a salt form.

f.pH-PARTITION HYPOTHESIS: :

f.pH -PARTITION HYPOTHESIS: The theory states that for drug compounds of molecular weight more than 100, which are primarily transported across the bio-membrane by passive diffusion, the process of absorption is governed by: 1. The dissociation constant pKa of the drug. 2. The lipid solubility of the un-ionized drug. 3. The pH at the absorption site.   A) Drug pKa and GI pH Amount of drug that exists in un-ionized form and in ionized form is a function of pKa of drug and pH of the fluid at the absorption site, and it can be determined by Handerson-Hasselbach equation:  For weak acids, pH = pKa + log [ionized] [un-ionized] …………………..(1.1)   % Drug ionized = 10 pH-pKa x 100 ……………..…… (1.2) 1+10 pH-pKa  For weak bases, pH = pKa + log [un-ionized] [ionized] …….(1.3) % Drug ionized = 10 pKa-pH x 100 ……(1.4) 1+10 pKa-pH

@:

@ If there is a membrane barrier that separates the aqueous solutions of different pH such as the GIT and the plasma, then the theoretical ratio R of drug concentration on either side of the membrane can be given by the following equations:   For weak acids,   R a = C GIT = 1+10 pHGIT-pKa C plasma 1+10 pHplasma-pKa ………. (1.5) For weak bases, R b = C GIT = 1+10 pKa-pHGIT C plasma 1+10 pKa-pHplasma ………. (1.6)   B) Lipophilicity and Drug absorption :  The lipid solubility of the drug is determined form its oil/water partition co-efficient (Ko/w) value, whereby the increase in this value indicates the increase in percentage drug absorbed.   Ko /w = Distribution of the drug in the organic phase ( octanol ) Distribution of the drug in the aqueous phase …………. (1.7)

Limitations pH partition hypothesis: :

Limitations pH partition hypothesis : a) Presence of Virtual Membrane pH: There is a presence of virtual membrane pH or the micro-climate pH, different from the luminal pH which exists at the membrane surface. b) Absorption of the ionized drug: Despite of the assumption that only un-ionized and lipophilic drugs are absorbed to a greater extent, some drugs e.g. Morphinan derivatives which are much more ionized are absorbed passively owing to their very high lipophilicity. c) Influence of the GI surface area and residence time of the drug: Irrespective of the GI pH and degree of ionization, both acidic and basic drugs are more rapidly absorbed from the intestine, primarily because of its large surface area and secondly, because of the long residence time of the drug in the intestine. d) Presence of Aqueous Unstirred Diffusion Layer: The drugs having a large partition co-efficient can readily penetrate the lipid membrane but the diffusion through the unstirred water layer is the rate limiting step in their absorption. This applies in particular to high molecular weight fatty acids and bile acids.  

Drug permeability and absorption:

Drug permeability and absorption Most orally administerd drugs enter the systemic circulation by passive diffusion and their absorption is expressed mathematicallly by equation: M = P eff A C app t res M = amount of drug absorbed P eff = effective membrane permeability A =surface area available for absorption C app =apparent lumainal drug concentration t res =residence time of drug in GI lumen

g. drug stability :

g. drug stability A drug for oral use may destabilized either during its shelf life or in the GIT . Two major stability problems resulting in poor bioavailability of an orally administered drug are -degradation of the drug into inactive form, and interaction with one or more different component(s) either of the dosage form or those present in the GIT to form a complex that is poorly soluble or is unabsorbable. Destabilization of a drug during its shelf life and in GIT.

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